Brain amyloid peptide (A) is a requirement for the neuropathologic diagnosis of Alzheimer's disease (AD). Previous research has shown that A is also present in the peripheral blood. Although A blood levels have typically been found to be higher in AD patients, variability among subjects has confounded attempts to use this measure as an AD diagnostic. Studies by the applicant have demonstrated that some of the A in blood is bound to erythrocytes as part of a mechanism for clearing A to the liver for degradation. Two characteristics of this mechanism appear to be significantly altered in AD patients. Individual AD erythrocytes appear to be deficient in their ability to carry A, suggesting that the amount of A per erythrocyte might be a simple, inexpensive, relatively non-invasive way to diagnose AD. However, there are some 2-3 X 1013 erythrocytes in the circulation2many more than enough to compensate for individual erythrocyte deficits. Thus, if one looks at the total amount of A in the erythrocyte compartment, significantly increased values are found in AD patients, suggesting a second diagnostic approach. In addition, the applicant6s preliminary studies observed a significant correlation of the two erythrocyte A biodiagnostic measures with a common mental status test, the MMSE. If true, then a longitudinal study might show these measures to be biological markers of disease progression, something that would greatly facilitate clinical trials of new drugs. Finally, patients diagnosed with mild cognitive impairment (MCI), a presumptive early stage of AD in many cases, had erythrocyte A measures that substantially overlapped those of the AD group. It is possible, therefore, that the measures may be picking out those MCI patients in whom the conversion to AD is most imminent. Specific Aim. Test the hypothesis that erythrocyte Ab is A) a sensitive and specific AD diagnostic, B) a measure that presages the transition of MCI patients to AD, and/or C) a useful biomarker of disease progression. A total of 125 AD, 125 MCI, 125 nondemented normal elderly (ND), and 125 patients with a neurologic disorder other than AD (OND) will be recruited, evaluated, tested on six cognitive status measures, and blood sampled for assays of erythrocyte A levels. These procedures will be repeated annually, yielding baseline, 1, 2, and 3 year data on diagnostic, prognostic, and biomarker potential of the erythrocyte measures. In addition, it is projected that some 96 of the subjects will come to autopsy, providing a 3gold standard4 for evaluating true sensitivity and specificity of the biodiagnostic approaches. NIA has provided a bridge grant to the principal investigator to cover recruiting, baseline measures, and a pilot project to compare erythrocyte and CSF A in Alzheimer6s Disease Neuroimaging Initiative subjects. However, without the present project6s longitudinal and neuropathology components, any such data will remain promising but preliminary.